Authors: Rychly, Joachim; Nebe, Barbara

Source: Current Pharmaceutical Design, Volume 12, Number 29, October 2006 , pp. 3799-3806(8)

Publisher: Bentham Science Publishers

Abstract:

The interaction of leukocytes with the vessel endothelium to facilitate the extravasation into the tissue represents a key process of the body's defense mechanisms. Excessive recruitment of leukocytes into the inflamed tissue in chronic diseases like autoimmune disorders could be prevented by interfering with the mechanisms of leukocyte extravasation. Significant progress in elucidating the molecular basis of the trafficking of leukocytes from the blood stream to the extravascular tissue has been achieved that enables new strategies for therapeutic approaches. The multistep process of leukocyte rolling, firm adhesion and transmigration through the endothelial wall is facilitated by a dynamic interplay of adhesion receptors on both leukocytes and endothelial cells as well as chemokines. In preclinical studies using various animal models, promising results have been received demonstrating that blocking of adhesion receptors of the selectin and integrin families improved the inflammation process in models of ulcerative colitis, autoimmune encephalomyelitis or contact hypersensitivity. In addition to the targeting of adhesion receptors by antibodies, small molecules that mimic epitopes of adhesion receptor ligands have been developed and successfully applied in animal models. Clinical studies revealed a limited response using antibodies to selectins or LFA-1 integrins compared with animal models. However, using humanized antibodies to the α4- integrin subunit significant efficacy has been demonstrated in autoimmune diseases like psoriasis, multiple sclerosis and inflammatory bowel disease.

Keywords: Autoimmune disease; integrin; leukocyte; endothelium; rolling; adhesion receptors; inflammation; antibody therapy

Document Type: Research article

Affiliations: 1: Experimental Research Centre and Department of Internal Medicine, University of Rostock, Ernst-Heydemann-Str. 6, 18055 Rostock, Germany.

Publication date: 2006-10-01

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• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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